Amino-acylamino-acylamino-penicillanic acids



3,268,517 AMINO-ACYLAMINO-ACYLAMINO- PENICILLANiC ACIDS Norman H. Grant, Wynnewood, and Harvey E. Album,

West Chester, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 7, 1964, Ser. No. 358,089 12 Clahns. (Cl. 260239.1)

This invention relates to new synthetic penicillins having potent activity against Gram-negative and Gram-positive microorganisms.

In our copending patent application Ser. No. 353,574, filed March 20, 1964, and of which the present application is a continuation-in-part, there is disclosed a novel method for preparing amino-acylamino-acylamino-penicillanic derivatives.

With the use of the method described in the said copending application, there has also been discovered a series of new penicillanic acid derivatives having the formula:

NH O=C-N-C-C OH i H e where n=2 to 9; and Y is of the group consisting of:

(1) R CH0 o where R is of the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkaryl, and substituted alkaryl; and

R is of the group consisting of alkyl and aryl;

where R R R and R are of the group consisting of hydrogen, alkyl, nitro, sulfo, amino, halo and hydroxy;

R and R R and R R and R when respectively joined, complete a ring of the group consisting of aryl and alicyclic; and

R is of the group consisting of hydrogen and lower alkyl;

where R R R and R are of the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halo, amino and nitro;

where 21:1 to 5, and R is of the group consisting of (a) hydrogen, alkyl, and

United States Patent 0 in Which case A is a second residue of the penicillanic acid derivative of Formula I above, and n'=l to 5;

where R is of the group consisting of hydroxy and alkyl, and n=2 to 7; and

NH: where n=1 to 4.

The new compounds of the series defined above show desirable broad spectrum antibacterial activity and are useful as therapeutic agents in poultry and mammals, including man, in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria, upon either parenteral or oral administration. They also have use as nutritional supplements in animal feed.

The general process for preparing the aforesaid novel amino-acylamino-acylamino-penicillanic acids is described and claimed in said copending application and comprises generally the reaction of a 4-substituted-Z,S-oxazolidinedione (also known as an N-carboXy-amino acid anhydride) with a 6-(amino-acylamino)-penicillanic acid under controlled conditions. Methods for the preparation of the N-carboxy amino acid anhydride and 6-(amino-acylamino) penici-llanic acid reactants suitable for use in the process are also described in or referred to in said copending application.

In a preferred method for preparing the amino-acylamino-acylamino-penicillanic acids of the present invention, the 4-substituted-2,5-oxazolidinedione chosen is reacted with the selected 6-(ot-amino-acylamino)penicillanic acid in approximately equimolar quantities in a cold aqueous solution in a pH range from about 3.8 to about 7.4 and preferably in the range 4.77.0. The mixture is stirred for several hours at a temperature from just above the freezing point of the aqueous mixture to about 37 C., and preferably in the range 010 C. Although not essential, it may be preferred to include a buffer having an ionic strength of about 0.02, preferably about 0.3, to aid in keeping the reaction mixture within the required pH range. Suitable buffers for maintaining the desired pH may be any mixture of organic or inorganic water-soluble acids, bases, or salts such as sodium acetate-acetic acid, calcium acetate-acetic acid, pyridine-acetic acid, formic acid-ammonia, etc. Alternatively, the reaction mixture may be maintained within the requisite pH range by areful addition of a base such as NaOH or the like.

The following examples are illustrative of the invention, but are not to be considered necessarily limitative thereof.

EXAMPE I 6- [1- (D-Z-aminmZ-phenylacetamido cyclobutanecarboxamia'o] penicilltmic acid Mix 376 mg. (1.2 millimoles) of 6-(1-aminocyclobutanecarboxamido)penicillanic acid with 212 mg. (1.2 millimoles) of D-phenylglycine-N-carboxyanhydride in 30 ml. of ice-cold water. Stir at l2 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against Staph. aureus and E. coli.

3 EXAMPLE II 6-[]- (D-2-amino-4-methylvaleramido cyclopentanecarboxamz'do] penicillanic acid Staph. aureus and E. coli.

EXAMPLE III When in the procedure of Example 11, the N-carboxyanhydride of D-leucine is replaced by 1.6 millimoles of the N-carboxanhydride of respectively, the following corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced:

(1 6-[1-(D-2-amino-phenylacetamido)cyclopentanecarboxamido] penicillanic acid (2) 6-[1-(D-2-amino-3-phenylpropionarnido)cyclopentane carboxamido] penicillanic acid (3) 6-[1-(L-2-arnino-3 -phenylpropi-onamido cyclopentane carboxamido1penicillanic acid (4) 6-[ 1-(1-aminocyclopentanecarboxamido)cyclopentanecarboxamido]penicillanic acid (5 6-[1-(2-aminobenzamido)cyclopentanecarboxamido] penicillanic acid (6) 6-[1-(Z-amino-S-nitrobenzamido)cyclopentanecarboxamidojpeni-cillanic acid (7 6-[ 1- (D-a-aminoindole-3 -propionamido cyclopentanecarboxamido] penicillanic acid (8) 6-[1-(L-u-aminoindo1e-3 -propionarnido cyclopentanecarboxamido]penicillanic acid (9 6-[ 1- (DL2-ami-no-N-methyl-2-phenylacetamido cyclopentanecarboxamido] penicillanic acid 10) 6-[1-(2-anilinoacetamido)cyclopentanecarboxamido]penicillanic acid (11) 6-[1-(L-2-pyrrolidinecarboxamido)cyclopentanecarboxamido1penicillanic acid 12) 6-[ 1- (DL-2-amino-2-o-ethoxyphenylacetamido cyclopenanecarboxamido penicillanic acid (13) bis[6-(1-[L-3-thio-2-aminopropionamido]cyclopentanecarboxamido)penicillanic acid] 14) 6-[1-(Z-aminoacetamido)cyclopentanecarboxamido]penicillanic acid 15) 6-[1-(2-amino-5-chlorobenzamido)cyclopentanecarboxamido1penicillanic acid 16) 6-[1-(Z-amino-5-methylbenzamido)cyclopentanecarboxamido] penicillanic acid EXAMPLE IV When in the procedure of Example I, the N-carboxyanhydride of D-phenylglycine is replaced by 1.2 millimoles of the N-carboxyanhydride of (1) 1-aminocyclopropanecarboxylic acid (2) 1-aminocyclodecanecarboxylic acid the corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced.

EXAMPLE V When in the procedure of Example I, the 6-(1-aminocyclobutanecarboxamido)penicillanic acid is replaced by 1.2 millimoles of 6-(1-aminocyclopropanecarboxamido) penicillanic acid, the corresponding penicillin product, active against both Gram-positive and Gram-negative microorganisms, is produced.

EXAMPLE VI When in the procedure of Example I, the 6-(1-aminocyclobutanecarboxamido)penicillanic acid is replaced by 1.2 millimoles of 6-(1-aminocyclodecanecarboxamido) penicillanic acid, the corresponding penicillin product, active against both Gram-positive and Gram-negative microorganisms, is produced.

As will be understood by those skilled in the art, the compounds of the invention may be utilized in their acid form or in the form of the therapeutically-active salts thereof, e.g., the sodium or potassium salts, or hydrochloride, etc, or in the form of the pharmaceutically-acceptable acid-addition salts prepared by the reaction of the penicillin compounds with an amine or diamine base, e.g., procaine, or various N,N-disubstituted alkylenediamines, such as N,N-dibenzylethylenediamine, etc.

We claim:

1. A compound of the formula:

NH O=ONC-COOH l H Y where n=2 to 9; and Y is of the group consisting of:

1 R1CHC 0 NE i where R is of the group consisting of hydrogen, lower alkyl, phenyl, (lower)alkylphenyl, (lower)alkoxypheny1,

aminophenyl, nitrophenyl, chlorophenyl, indolo(lower)alkyl, (lower)alkylindolo(lower) alkyl, and (lower) alkoxyindolo (lower) alkyl; and

R is of the group consisting of hydrogen, lower alkyl,

a naphthylene Where where R R R and R are of the group consisting of hy- 11:1 to 2.

drogen alkyl E9 mm) (51110); 1 2. 6 [1 (D 2 amino 2 pheny1acetamido)cyc1o- R and R when oined complete a naphthylene ring;

butanecarboxamido]penicillanic acid.

3. 6 [1 (D 2 amino 4 methy1va1erarnido)cyc1o pentanecarboxamido]penicillanic acid.

and

5 R is of the group consisting of hydrogen and alkyl;

(4) f 4. 6 [1 (D 2 amino 3 pheny1pr0pionarnido)cyf CHPCH CO clopentanecarboxarnido]penici11anic acid.

I 5. 6 [1 (L 2 amino 3 pheny lpropionamidofly- R NH2 clopentanecarboxamido]penicillanic and.

I 6. 6 [1 (1 aminocy clopentanecarboxarnido)cyclo- 4 pentanecarboxamido]peniclllanic acid.

Where 7. 6 [1 (D a aminoindole 3 propionamido)cy- 1 2 3 and 4 are f the group consisting f 15 clopentanecarboxamido]penicillanic acid.

drogen, lower alkyl and lower alkoxy; 8. bis [6 (1 [L 3 thio 2 aminopropionarnido] (5) cyclopentanecarboxarnido)penicillanic acid].

A 9. 6 [1 (DL 2 methylarnino phenylacetanii- Where do)cyclopentanecarboxarnido]penicillanrc acid. 11:1 to 5, and 10. 6 [1 (2 anilinoacetamido)cyclopentanecarbox- R is of the group consisting of hydrogen and lower amldo] pemclnamc acld' k 11. 6 [1 (2 pyrrolidinecarboxamido) cyclopentane- (6) R carboxamido1penicil1anic acid.

12. 6 [1 (L ocaminoindole 3 propionamido)cy- (grim H clopentanecarboxamido] penicillanic acid. No references cited.

Where R is of the group consisting of hydroxy and alkyl, ALEX MAZEL, Primary Examiner 7; and HENRY R. JILES, Examiner.

NH JAMES W. ADAMS, 111., Assistant Examiner. 

1. A COMPOUND OF THE FORMULA: 